a study of mesothelin-targeted car t-cell therapy in people with esophagogastric cancer

Conditions: Mesothelin Positive; Mesothelin-Expressing Tumors; Esophageal Adenocarcinoma; Esophageal Adenocarcinomas; Esophagogastric Adenocarcinoma; Peritoneal Carcinomatosis; Breast Neoplasms; Diabetes Mellitus

Summary: participants will have a sample of their white blood cells, called t cells, collected using a procedure called leukapheresis. the collected t cells will be sent to a laboratory at memorial sloan kettering to be changed (modified) to become msln-targeted car t cells, the car t-cell therapy that participants will receive during the study. participant study therapy will take about 3-4 weeks.


Eligibility criteria:
inclusion criteria: * aged ≥18 years * diagnosis of pathologically confirmed eg adenocarcinoma * diagnosis of metastatic or recurrent disease * ecog performance status of 0-1 * life expectancy of ≥4 months inclusion criteria for leukapheresis: * written informed consent for the study (from participant) * life expectancy of ≥4 months * ecog performance status of 0-1 * histologic diagnosis that \& \>25% of the tumor expresses msln by ihc analysis. archival tissue obtained up to 2 years before study enrollment is acceptable. ihc testing of a cell block from cytology (e.g., ascitic fluid) is acceptable if approved by the study pathologist. if adequate archival tissue is not available at screening, a fresh tumor biopsy should be obtained * stage iv disease with gross peritoneal carcinomatosis on imaging and/or microscopic peritoneal involvement by cytology or noted during diagnostic laparoscopy * disease progression or treatment intolerance after receiving at least 1 treatment regimen in the metastatic setting; patients with disease recurrence within 6 months of completing curative systemic therapy (chemotherapy, chemoradiation or adjuvant immunotherapy) are also eligible * patients with her2 positive disease must have received ≥1 line of anti-her2 based therapy * at least 1 measurable or evaluable lesion per recist 1.1. screening imaging must be obtained within 6 weeks of signing the informed consent form * completion of systemic therapy at least 7 days before leukapheresis o immune checkpoint inhibitor therapy must be completed at least 14 days before leukapheresis * lab requirements (hematology): * absolute neutrophil count ≥1.0 k/mcl * hemoglobin ≥9 gm/dl * platelet count ≥75 k/mcl * blood product transfusion or growth factor support cannot occur within 7 days of testing * lab requirements (serum chemistry): * bilirubin ≤1.5× upper limit of normal (uln) * serum alanine aminotransferase and serum aspartate aminotransferase (alt/ast) level ≤3× uln * calculated clearance of ≥50 ml/min by cockcroft-gault equation * negative screen for infectious disease markers, including hepatitis b core antibody, hepatitis b surface antigen, hepatitis c antibody, hiv 1-2 antibody, htlv antibody and syphilis antibody o note: patients with a history of hepatitis b virus infection are eligible if the hepatitis b viral load is undetectable. patients with a history of hepatitis c virus infection who were treated for hepatitis c and cured are eligible if the hepatitis c viral load is undetectable * serum pregnancy test with negative result at screening and preconditioning and must be willing to use effective and reliable contraception for at least 12 months after t cell infusion (for female participants of childbearing age) * resolution of all acute toxic effects of any previous therapeutic or palliative chemotherapy, radiotherapy, or surgical procedures to grade ≤1 (ctcae v5.0), except for neuropathy and alopecia inclusion criteria for lymphodepleting chemotherapy/car t cell infusion * life expectancy of ≥4 months * ecog performance status of 0-1 * at least 1 measurable or evaluable lesion per recist 1.1. screening imaging must be obtained within 4 weeks before the date of lymphodepletion * completion of systemic therapy at least 14 days before lymphodepleting chemotherapy o immune checkpoint inhibitor therapy must be completed at least 28 days before lymphodepleting chemotherapy * lab requirements (hematology): * absolute neutrophil count ≥1.5 k/mcl * hemoglobin ≥8 gm/dl * platelet count ≥75 k/mcl * lab requirements (serum chemistry): * bilirubin ≤1.5× upper limit of normal (uln) * serum alanine aminotransferase and serum aspartate aminotransferase (alt/ast) level ≤3× uln * calculated clearance of ≥50 ml/min by cockcroft-gault equation * serum pregnancy test with negative result within 7 days of planned lymphodepletion date and must be willing to use effective and reliable contraception for at least 12 months after t cell infusion (for female participants of childbearing age) * resolution of all acute toxic effects of any previous therapeutic or palliative chemotherapy, radiotherapy, or surgical procedures to grade ≤1 (ctcae v5.0), except for neuropathy and alopecia participant exclusion criteria exclusion criteria for leukapheresis or lymphodepleting chemotherapy/car t cell infusion: participants are excluded from enrollment if any of the following criteria apply: * pregnant or lactating * hiv, active hepatitis c virus, or active hepatitis b virus infection, as determined by quantitative pcr (patients who have undergone negative testing prior to leukapheresis do not require repeat testing) * receiving therapy for concurrent active malignancy * note: patients receiving treatment for in situ skin malignancies are not excluded. * patients with any malignancy diagnosed \&gt;3 years before that is thought to be curatively treated and/or has a low risk of recurrence are eligible. patients may continue to receive adjuvant therapy at the time of study enrollment (e.g., adjuvant hormonal therapy for curatively treated breast cancer). * known hematologic malignancy requiring treatment in the preceding 5 years or a known history of lymphoid malignancy * previous receipt of car t cell therapy or any other cellular therapy * previous mesothelin-directed therapy any major abdominal surgery (laparotomy with resection of gastrointestinal tract or organ resection) that is completed \&lt;28 days before study enrollment. patients who have undergone diagnostic laparoscopy can be included in the study without regard to timing * untreated or active central nervous system (cns) metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control). patients with a history of treated cns metastases are eligible if all of the following criteria are met: * radiographic demonstration of improvement upon completion of cns-directed therapy and no evidence of interim progression between completion of cns-directed therapy and the screening radiographic study * completion of radiotherapy ≥4 weeks before the screening radiographic study * active autoimmune disease that has required systemic treatment within 1 year before leukapheresis (with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) o note: replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed. * receiving daily systemic corticosteroids ≥10 mg of prednisone daily or equivalent or receiving immunosuppressive or immunomodulatory treatment * any of the following cardiac conditions: * new york heart association stage iii or iv congestive heart failure * myocardial infarction ≤6 months before enrollment * history of myocarditis * serious uncontrolled cardiac arrhythmia, unstable angina, or uncontrolled infection * left ventricular ejection fraction ≤40% * active interstitial lung disease/pneumonitis or a history of interstitial lung disease/pneumonitis requiring treatment with systemic steroids * baseline pulse oximetry \&lt;90% on room air at the screening time point * known active infection requiring antibiotic treatment 7 days before leukapheresis o note: treatment can be delayed at the discretion of the treating physician to allow the patient to recover from the infection. * any other medical condition, e.g. fever \&gt;38.0 degrees c, that, in the opinion of the pi, may interfere with the subject's participation in or compliance with the study * receipt of live, attenuated vaccine within 8 weeks before the planned lymphodepleting chemotherapy date * deemed to be noncompliant by the study team for administration of a high-risk treatment agent and for close follow-up after treatment as required by the protocol

Keywords: mesothelin positive mesothelin-expressing tumors esophageal adenocarcinoma esophageal adenocarcinomas esophagastric adenocarcinoma peritoneal carcinomatosis car t-cell therapy 24-214